Uptake of cholesterol by cells of the blood vessel wall is an integral part of heart disease (atherosclerosis). Cholesterol-filled cells ("foam cells") burst and die, attracting scavenger cells, promoting an inflammatory reaction and contributing to the fatty part of the atherosclerotic plaque which may eventually break off or form a focus-promoting thrombosis.
In other pathological conditions including diabetes, thyroid hormone deficiency, renal failure and some inherited hyperlipidemias, LDL free cholesterol is unusually high, while HDL levels are markedly reduced. This suggests that abnormal regulation of cellular uptake of cholesterol is a component in the etiology of these disease states.
Cellular free cholesterol levels are normally well buffered against changes in external (serum) concentrations of lipoprotein free cholesterol (FC) through a variety of influx and efflux mechanisms (Fielding (1992) FASEB J., 6: 3162-3168). High affinity low-density lipoprotein (LDL) receptor-mediated endocytosis represents one important mechanism for the regulation of cellular sterol. However, in most nonhepatic cells these receptors are markedly down-regulated by even the low concentrations of LDL typical in normal plasma. Similarly, the synthesis of new cholesterol (Goldstein et al., Proc. Natl. Acad. Sci. (USA), 75: 1877-1881 (1978)) is also down-regulated by low concentrations of LDL. Thus, neither receptor-mediated endocytosis nor cholesterol synthesis appear to be important mechanisms in cholesterol regulation by most mammalian cells.
A third mechanism, selective transfer of esterified cholesterol (EC) from LDL has been demonstrated (Reaven et al. (1986) J. Clin. Invest., 77: 1971-1974), but this pathway seems to be active mainly on steroidogenic cells. Despite the low rates of cholesterol uptake via these pathways, high rates of FC efflux, unaccounted for by these mechanisms, continue to be observed in the presence of plasma lipoproteins (Fielding & Fielding (1981) Proc. Natl. Acad. Sci. (USA), 78: 3911-3914; Johnson et al. (1991) Biochim. Biophys. Acta, 1085: 273-298; Kawano et al. (1993) Biochemistry, 32: 5025-5028). These considerations suggest there is substantial recycling of FC between the cell surface and the extracellular medium.
Several laboratories have observed that the efflux of FC from peripheral cells to medium (e.g., serum) lipoprotein acceptors is primarily to high-density lipoproteins (HDL) (Francone et al. (1990) J. Lipid Res., 31: 2195-2200; Huang et al. (1993) Arterioscler. Thromb., 13: 445-458). The origin of this free cholesterol (FC) and the mechanism by which it may have originally entered the cell have been little studied, even though it could be a significant contributor to cholesterol homeostasis. Each of the major plasma lipoproteins (HDL, LDL and very low-density lipoprotein, VLDL) is a potential source of FC for influx. Simple diffusion, or molecular collision accounts for the transfer of cholesterol between lipoproteins and erythrocytes (Steck et al. (1988) J. Biol. Chem., 263: 13023-13031; Johnson et al. (1991) Biochim. Biophys. Acta, 1085: 273-298). However, additional mechanisms seem likely to contribute in fibroblasts, vascular smooth muscle cells and macrophages. In these cells (unlike erythrocytes) efflux is markedly inhibited by protease pretreatment of the cell surface (Kawano et al. (1993) Biochemistry, 32: 5025-5028).